The ability to detect rare mutations in a population of sequences is enabling for a wide range of molecular studies that relate shifts in genotype and phenotype to selective pressures. Although recent technologies have enabled the analysis of entire genomes for common variation, it is still very challenging to detect rare variants in a sample. This proposal aims to develop a new approach to detect rare genetic variants using next- generation sequencing. Our approach has implications for the development of diagnostic and theranostic tests, and the development of novel drugs to treat infectious diseases and cancer. PUBLIC HEALTH RELEVANCE: There are over 200 diseases that are caused by mutations in the mitochondrial genome. Many of these mutations occur at a low frequency and are difficult to detect. By developing a powerful new method to detect rare variants, we aim to address an important unmet medical need.